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Mutational Analysis of the Adaptor Protein 2 Sigma Subunit (AP2S1) Gene: Search for Autosomal Dominant Hypocalcemia Type 3 (ADH3)

Lookup NU author(s): Professor Simon PearceORCiD


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Context: Autosomal dominant hypocalcemia (ADH) types 1 and 2 are due to calcium-sensing receptor (CASR) and G-protein subunit-alpha 11 (GNA11) gain-of-function mutations, respectively, whereas CASR and GNA11 loss-of-function mutations result in familial hypocalciuric hypercalcemia (FHH) types 1 and 2, respectively. Loss-of-function mutations of adaptor protein-2 sigma subunit (AP2 sigma 2), encoded by AP2S1, cause FHH3, and we therefore sought for gain-of-function AP2S1 mutations that may cause an additional form of ADH, which we designated ADH3.Objective: The objective of the study was to investigate the hypothesis that gain-of-function AP2S1 mutations may cause ADH3.Design: The sample size required for the detection of at least one mutation with a greater than 95% likelihood was determined by binomial probability analysis. Nineteen patients (including six familial cases) with hypocalcemia in association with low or normal serum PTH concentrations, consistent with ADH, but who did not have CASR or GNA11 mutations, were ascertained. Leukocyte DNA was used for sequence and copy number variation analysis of AP2S1.Results: Binomial probability analysis, using the assumption that AP2S1 mutations would occur in hypocalcemic patients at a prevalence of 20%, which is observed in FHH patients without CASR or GNA11 mutations, indicated that the likelihood of detecting at least one AP2S1 mutation was greater than 95% and greater than 98% in sample sizes of 14 and 19 hypocalcemic patients, respectively. AP2S1 mutations and copy number variations were not detected in the 19 hypocalcemic patients.Conclusion: The absence of AP2S1 abnormalities in hypocalcemic patients, suggests that ADH3 may not occur or otherwise represents a rare hypocalcemic disorder.

Publication metadata

Author(s): Rogers A, Nesbit MA, Hannan FM, Howles SA, Gorvin CM, Cranston T, Allgrove J, Bevan JS, Bano G, Brain C, Datta V, Grossman AB, Hodgson SV, Izatt L, Millar-Jones L, Pearce SH, Robertson L, Selby PL, Shine B, Snape K, Warner J, Thakker RV

Publication type: Article

Publication status: Published

Journal: Journal of Clinical Endocrinology and Metabolism

Year: 2014

Volume: 99

Issue: 7

Pages: E1300-E1305

Print publication date: 01/07/2014

Online publication date: 07/04/2014

Acceptance date: 18/03/2014

ISSN (print): 0021-972X

ISSN (electronic): 1945-7197

Publisher: Endocrine Society


DOI: 10.1210/jc.2013-3909


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Funder referenceFunder name
National Institute for Health Research Oxford Biomedical Research Centre
G1000467United Kingdom Medical Research Council
G9825289United Kingdom Medical Research Council